Fetal programming of adult disease: modelling causes and effects of a metabolic phenotype in polycystic ovary syndrome (PCOS)
3-Year PhD Studentship in Reproductive Health Sciences
Primary Supervisor - W. Colin Duncan
Project - Fetal programming of adult disease: modelling causes and effects of a metabolic phenotype in polycystic ovary syndrome (PCOS)
The Medical Research Council (MRC) Centre for Reproductive Health (MRC-CRH) conducts research into conditions that affect reproductive fitness and the health of male and female reproductive organs including infertility, endometriosis and premature birth. The Centre brings together scientists who have outstanding strengths in reproductive biology, stem cells, inflammation, development, hormonal disease and imaging. We provide a rich environment for training of clinical and non-clinical scientists and a vibrant programme of activities aimed at encouraging public engagement in science.
Three 3-year PhD Studentships will be available in September 2013 to outstanding science graduates wishing to pursue a career in Reproductive Health Sciences. The studentship will cover tuition fees at the UK/EU rate, a stipend (currently £13,726) with a rise each year to match inflation. This PhD Programme seeks to attract the best students from across the UK and EU to join our internationally recognised research community of Reproductive Health Scientists in Edinburgh. The Centre has a thriving postgraduate community of more than 30 MSc and PhD trainees who are mentored by a postgraduate studies committee.
Applicants are expected to have a good honours degree in the sciences (biological, chemical or physical), at least UK level of 2.1 or the equivalent from non-UK universities. A Master’s degree in relevant subject would be an advantage.
The Little France Campus
The Centre for Reproductive Health is located on the ground floor of the Queen’s Medical Research Institute on the University of Edinburgh’s Medical Campus at Little France. (http://www.ed.ac.uk/schools-departments/medicine-vet-medicine/about/little-france) The CRH enjoys close collaborative links with the other Centres on the Little France Campus including the MRC Centre for Inflammation Research (MRC-CIR); the British Heart Foundation Centre of Excellence in Cardiovascular Science (BHF-CVS) and the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM).
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women in their reproductive years affecting 7-8% of women. In addition to ovulatory dysfunction, women with PCOS have higher concentrations of circulating androgens and there is a marked association with dyslipidaemia, obesity, type II diabetes, heart disease and insulin resistance. Although there is a familial element to PCOS large genetic linkage studies have not identified a robust genotype. Whether the cause is genetic or environmental there is increasing evidence that it is programmed in fetal life. There is now a wealth of data involving the characterisation of primates and sheep exposed to increased androgens during pregnancy. The offspring of mothers exposed to testosterone for part of pregnancy had the hormonal, metabolic and ovarian phenotypes of PCOS.
We have refined an ovine model of fetal programming of a PCOS-like condition. As well as treating pregnant ewes with testosterone we have directly injected the fetus with different steroids to dissect the effects of steroid manipulation on the developing fetus. We have a large sample bank of female and male fetal, lamb and adult tissue where steroid exposure of the developing the fetus has been altered. We have shown that there are changes in the androgenic capacity of the adult adrenal and ovary and well as insulin resistance, fatty liver and increased hepatic insulin-like growth factor secretion. This project builds on these robust observations and initially utilises a large sample bank of tissue that is already in place.
This project investigates the causes and consequences of the abnormal metabolic phenotype in the ovine model of PCOS. Initially the project will focus on liver:
When and how does the increase in hepatic IGF-1 expression develop?
• What is the ontogeny of the hepatic IGF system in fetal and adult life?
• Is there sexual dimorphism in the hepatic IGF system?
• Is it programmed by stress, androgen or estrogen?
• Is growth hormone or the hepatic response to growth hormone altered?
• Are hepatic IGF system genes differentially methylated?
A full training will be given in experimental design, student supervision and teaching, data analysis and data presentation and publication. The specific techniques involved in this project include working with large animal experimental models, assays, quantification and localisation of RNA and protein and epigenetic modification of DNA. These techniques are well established within the laboratory giving a very high change of early success and publication. There is an excellent track record for PhD training and success within the laboratory.
How to Apply
For application, please submit a copy of:
• A curriculum vitae
• A ‘statement of purpose’ outlining your reasons for undertaking this programme of study and how you see it affecting your career plan, together with an indication of which project you are interested in (see list below)
• 3 academic references should email/send letters on your behalf to: [Email Address Removed]
PLEASE NOTE Applications sent directly to project supervisors may not be counted.
The closing date to apply for these studentships is Monday 11 March 2013.
If you have any questions regarding the programme please contact the programme secretary [Email Address Removed]
Abbott DH et al., (2005) Hum Reprod Update, 11: 357-374.
Hogg K et al., (2011) PLoS One, 6: e24877.
Hogg K et al., (2012) Endocrinology, 153: 450-461.
Padmanabhan V and Veiga-Lopez A (2013) Mol Cell Endocrinol, [Epub ahead of print].
Rae MT et al., (2013) PLoS One, 8: e56263.